Thermally Triggered Release and Nonthermal Antitumor Effects of Magnetic Thermosensitive Lipid–Polymer Hybrid Nanoparticles in Hep G2 Cells Under Alternating Magnetic Field

ABSTRACT This study constructed a novel magnetic thermosensitive lipid–polymer hybrid nanoparticles (MTHNPs) system triggered by alternating magnetic field (AMF). The system employs poly (lactic‐co‐glycolic acid) (PLGA) and phase‐change material 1‐tetradecanol (Tet) as carriers, loaded with superparamagnetic iron oxide (SPIO), and stabilized via phospholipid coating. Tet acts as a “thermosensitive switch”, undergoing phase transition under AMF‐induced localized nanoheating to controllably release SPIO. Experimental results showed that MTHNPs could be effectively taken up by human hepatocarcinoma Hep G2 cells and localized in lysosomes. Under conditions that did not induce significant bulk temperature increase, the combined treatment of MTHNPs and AMF demonstrated significant synergistic antitumor effects in Hep G2 cells, including significant inhibition of cell viability, induction of apoptosis, significant increase of reactive oxygen species (ROS), and rapid onset of cell membrane impairment. Furthermore, mechanism studies reveal that this effect primarily stems from the synergistic combination of multiple biological effects mediated by nonthermal mechanisms such as magnetomechanical force after SPIO release. Collectively, this research provides novel insights for developing nonthermal therapeutic strategies based on physical triggering and tumor microenvironment regulation. Summary This study developed magnetic thermosensitive lipid–polymer hybrid nanoparticles (MTHNPs) that enable alternating magnetic field (AMF)‐triggered release of superparamagnetic iron oxide (SPIO). Without significant bulk heating, the treatment synergistically inhibited Hep G2 cells viability, induced apoptosis, and caused membrane damage via non‐thermal mechanisms, offering a novel strategy for hepatocellular carcinoma therapy.